CD22 is a B-lineage restricted phosphoprotein that plays a key modulatory role in B-cell responses. CD22 associates with the B cell antigen receptor complex (BCR) and is rapidly phosphorylated on tyrosyl residues following surface immunoglobulin (sIg) cross-linking. Tyrosyl-phosphorylated CD22 recruits protein tyrosine kinases (PRKs) to the BCR, and also binds to and activates SHP-1, a protein tyrosine phosphatase (PTP) that negatively regulates BCR-mediated signaling. Genetic analyses, in inbred mice, maps the CD22 locus to a region of chromosome 7 that has been linked to the genesis of lupus-like disease. Recent data from the Neel laboratory provides tantalizing evidence to suggest that one of two alleles, encoding mouse CD22, may be defective in regulating PTK and PTP pathways within B cells. Such a defect could lead to anomalous B cell signaling, potentially resulting in autoantibody production or other immune dysfunction. Preliminary analysis suggest that allele-specific B cell lines, which lack expression of this CD22 allele, are defective in the association of SHP-1 and CD22. Moreover, these cells exhibit aberrant tyrosyl phosphorylation of Be cell substrates. By examining CD22 allelic-specific and CD22 null isolates of WEHI-231 cells, as well as primary B cells from autoimmune mice, I will explore the hypothesis that one of two alleles encoding CD22 is defective in B cell signaling. The domains responsible for the functional differences between CD22 allelic isoforms will be identified. In addition, the consequences of expressing variant CD22 allelic-proteins for B cell signaling will be explored in vivo using a transgenic model. Together, these findings provide a framework to explore the exciting possibility that an allelic variant of CD22 contributes to the development of B cell abnormalities, and potentially autoimmune disease, in mouse and man.